Gestational Hypertension as a Mediator of Prenatal Ozone Exposure and Term Low Birth Weight: Birth Cohort Study

Abstract Background Ambient ozone (O 3 ) exposure has been found to be associated with gestational hypertension, which, in turn, increases the risk of term low birth weight (LBW). As such, gestational hypertension acts as a potential mechanism mediating restricted fetal growth; however, few epidemiological studies have quantified this specific mediation pathway. Objective This study aims to examine whether gestational hypertension serves as a mediator of the association between prenatal O 3 exposure and term LBW. Methods We conducted a population-based cohort study using the Cheeloo Lifespan Electronic Health Research Data-library, including 3,394,739 singleton term live births in Shandong Province, China, from January 1, 2016, to December 31, 2022. We used high-resolution spatiotemporal models based on residential addresses for exposure assessment. In addition to term LBW, we examined term small for gestational age (SGA) to capture fetal growth restriction while accounting for gestational age at birth. Given the low prevalence of these outcomes, we used logistic regression models where odds ratios approximated relative risks. A 4-step mediation analysis using logistic regression was conducted, followed by a counterfactual-based causal mediation analysis, to test the mediating role of gestational hypertension. Results The mean (SD) O 3 concentration was 113.90 (13.03) μg m –3 . Each IQR increase in O 3 was positively associated with the risks of term LBW (relative risk 1.055, 95% CI 1.034-1.077) and term SGA (relative risk 1.037, 95% CI 1.026-1.048). Using the traditional approach, gestational hypertension mediated 19.94% of the risk for term LBW and 13.41% for term SGA. Under the counterfactual framework, the contribution rates were 38.82% (term LBW) and 19.96% (term SGA) when excluding exposure-mediator interaction, and 35.15% (term LBW) and 18.82% (term SGA) when accounting for such interaction. Conclusions Our findings showed that gestational hypertension was a significant mediator of the association between O 3 exposure and risks of term LBW. Consequently, a multitiered strategy—encompassing stricter air quality standards, integrating O 3 risk education into routine prenatal care, and taking proactive measures to minimize personal exposure—is essential to prevent potential adverse impacts on developing fetuses and mothers.